Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Pharmaceutical Compositions
The present invention concerns pharmaceutical compositions comprising a pH-
dependent
drug compound, uses and processes for the manufacturing of such compositions.
pH-dependent drug compounds exhibit a significant pH-dependent solubility
along the
gastrointestinal tract. They are soluble at the low gastric pH expected in
fasted healthy
subjects. However, in a higher intestinal pH environment they may precipitate
and/or
dissolve incompletely. Additionally, food intake, medical treatment, and
pathophysiological
conditions may elevate the gastric pH and, consequently, drug dissolution may
be
decreased. Incomplete dissolution may result in highly variable inter-and
intra patient
bioavailability of the pH-dependent drug compound.
The incorporation of pH modifiers, e.g. organic acids, into an oral dosage
form modulates
the microenvironmental pH and thereby enhances the drug solubility and drug
dissolution. In
addition, pH-independent drug release can be achieved. However, pH modifiers
typically
exhibit a higher solubility at higher pH environments compared to the drug
compound,
diffuse out rapidly and consequently separate rapidly from the pH-dependent
drug
compound present in the solid dosage form. Polymers may be used to retard the
rapid
diffusion of pH modifiers thus maintaining the target pH inside the solid
dosage form.
However, the use of polymers typically result in modified release
formulations, e.g. with a
drug release over an extended period of time, e.g. over 10 hours and longer.
Complete
absorption of the drug compound from such modified release formulations may
highly
depend on the physiological conditions but also on the drug compound itself.
For example,
drug compounds that are absorbed only in a very specific, e.g. upper, part of
the intestinal
tract, e.g. the small intestine, may show a high inter- and intra subject
variability and
impaired bioavailability.
Accordingly, there is a need for pharmaceutical compositions comprising pH-
dependent drug
compounds with reduced inter- and intra subject variability and increased
bioavailability.
Surprisingly, the present inventors have identified improved pharmaceutical
compositions
comprising a pH-dependent drug compound and a pH modifier wherein the pH
modifier is
present inside the formulation e.g. over the entire dissolution time, e.g.
simultaneously
released together with the drug compound.
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In one aspect, the present invention provides a pharmaceutical composition
comprising a
pH- dependent drug compound, a pH modifier and a retarding agent, e.g. a
polymer, e.g. a
water-soluble polymer, wherein the drug release from the pharmaceutical
composition is
completed after a maximum dissolution time of 4 hours, e.g., within a
dissolution time of
about 1 to 4 hours, e.g. within 1 to 2, or 1 to 3 hours, or about 2 to 4, e.g.
2 to 3 hours, e.g.
upon contact with gastrointestinal juices.
In a further aspect of the invention, an additional enteric coating may be
applied, e.g., to
prevent any early diffusion of the drug and the acid in the stomach and/or to
suppress
individually varying stomach pH effects on dissolving the drug and the acid,
e.g. to ensure
uniform drug dissolution in the upper part of the intestinal tract, e.g. small
intestine.
In yet a further aspect the present invention provides for an isolation coat
between the acid
core and the enteric coating, e.g., to provide for a dissolution of the
enteric coat at an
intestinal pH of about >_ 5.5.
In yet a further aspect of the present invention, the pharmaceutical
composition is in form of
a multiparticulate system, e.g., minitablets or pellets. Such multiparticulate
systems may
show advantages over monolithic systems, e.g., improved transit
reproducibility and/or high
degree of dispersion in the digestive tract, resulting in reduced intra- and
inter-subject
variability and improved bioavailability.
These and other features, advantages and objects of the present invention will
be further
understood and appreciated by those skilled in the art by references to the
following
specification, claims and appended drawings.
Brief Description of the Drawings
The accompanying drawings, which are incorporated in and constitute a part of
the
specification, illustrate exemplary embodiments of the present invention.
FIG. 1 shows the simultaneous release rates of the drug and the pH modifier.
FIG. 2 shows the impact of pH modifiers on drug release.
FIG. 3 shows the drug release independent from the dissolution medium pH.
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The compositions of the invention provide for short-duration modified release
of a pH-
dependent drug compound, in particular in the upper part of the intestinal
tract, e.g. in the
small intestine, showing reduced inter- and intra patient variability and
improved
bioavailability.
Detailed Description of Invention:
As used herein, the term "drug" means any compound, substance, drug,
medicament or
active ingredient having a therapeutic or pharmacological effect, and which is
suitable for
administration to a mammal, e.g., a human. Such drugs should be administered
in a
"therapeutically effective amount".
As used herein, the term "therapeutically effective amount" refers to an
amount or
concentration which is effective in reducing, eliminating, treating,
preventing or controlling
the symptoms of a disease or condition affecting a mammal. The term
"controlling" is
intended to refer to all processes wherein there may be a slowing,
interrupting, arresting or
stopping of the progression of the diseases and conditions affecting the
mammal. However,
"controlling" does not necessarily indicate a total elimination of all disease
and condition
symptoms, and is intended to include prophylactic treatment.
The appropriate therapeutically effective amount is known to one of ordinary
skill in the art
as the amount varies with the therapeutic compound being used and the
indication which is
being addressed.
Drugs and salts thereof that are particularly suited for the present invention
are those that
are pH-dependent, in particular weakly basic drugs, e.g. any drug where the
solubility
difference between pH 1 and pH 6 is > 100.
The drug may be present in an amount up to about 60% by weight of the
composition, from
about 1% to about 60% by weight of the composition. It is intended, however,
that the choice
of a particular level of drug will be made in accordance with factors well-
known in the
pharmaceutical arts, including mode of administration and the size and
condition of the
subject.
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Suitable pH modifiers according to the invention include acids, e.g. inorganic
acids, e.g.
water-soluble inorganic acids that are solid at ambient temperature, for
example sulfamic
acid.
Suitable organic acids contain one or more acidic group, e.g. acidic groups
selected from
carboxylic and sulfonic acid groups, particularly those which are solid at
ambient
temperature.
Suitable water-soluble organic acids include water-soluble organic acids
selected from
mono, di- or polybasic carboxylic acids or mono, di or tri-sulfonic acids,
e.g. which are solid
at ambient temperature. Suitable solid water-soluble carboxylic acids include
aliphatic mono
or poly-carboxylic acids, e.g. containing from 2 to 8 carbon atoms,
particularly from 2 to 6
carbon atoms, e.g. all- or tricarboxylic acids containing from 4 to 6, e.g. 4
carbon atoms, e.g.
saturated or unsaturated. Examples of suitable solid water-soluble aliphatic
mono- carboxylic
acids include sorbic acid (2,4-hexandienoic acid). Examples of suitable solid
water-soluble
aliphatic di-carboxylic acids include adipic, malonic, succinic, glutaric,
maleic or fumaric acid.
The aliphatic carboxylic acid may be optionally substituted by one or more
groups, e.g. 1, 2
or 3 groups, which may be the same or different, selected from carboxy, amino
and hydroxy.
Suitable substituted solid water-soluble aliphatic carboxylic acids include
for example
hydroxy substituted aliphatic mono-carboxylic acids such as gluconic acid,
solid forms of
lactic acid, glycolic acid or ascorbic acid; hydroxy substituted aliphatic di-
carboxylic acids
such as malic, tartaric, tartronic (hydroxymalonic), or mucic (galactaric)
acid; hydroxy 2s
substituted aliphatic tri-carboxylic acids, for example citric acid; or amino
acids carrying an
acidic side chain, such as glutamic acid or aspartic acid.
Suitable aromatic carboxylic acids include water-soluble aryl carboxylic acids
containing up
to 14 carbon atoms. Suitable aryl carboxylic acids comprise an aryl group, for
example a
phenyl or naphthyl group which carries one or more carboxyl groups, e.g. 1, 2
or 3 carboxy
groups. The aryl group is optionally substituted by one or more groups, e.g.
1, 2 or 3 groups,
which may be the same or different, selected from hydroxy, (1-4C) alkoxy, e.g.
methoxy, and
sulfonyl. Suitable aryl carboxylic acids include benzoic, phthalic,
isophthalic, terephthalic or
trimellitic acid (1,2,4- benzenetricarboxylic acid).
Preferably the pH modifier is selected from citric acid, fumaric acid,
succininc acid, adipic
acid and maleic acid. Preferably fumaric acid is used.
pH modifiers that are particularly suited for the present invention are those
that change the
microenvironmental pH towards being more acidic thereby increasing the release
rate of the
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drug from the dosage form at pH values where the drug becomes difficultly
soluble, e.g.
insoluble.
The pH modifier comprises from about 1% to about 60% by weight of the
composition, e.g.,
from about 10% to about 40% by weight of the composition. The ratio of pH
modifier to drug
compound in the compositions of the invention may be from about 0.2 : 1 to
about 2: 1, e.g.
1:1.
As retarding agents, polymers, e.g. water soluble polymers, e.g. cellulose
derivatives, e.g.,
having a viscosity of greater than about 100 cps, e.g. having a viscosity of
between about
100 and about 100,000 cps may be used. Preferably water-soluble polMers may be
used.
Suitable polymers include but are not limited to cellulose derivatives, e.g.
methyl cellulose,
hydroxypropyl methyl cellulose, e.g. hydroxypropyl methyl cellulose k100LV, K
4 M, or
hydroxypropyl methyl cellulose K 15 M, hydroxypropyl cellulose, hydroxyethyl
cellulose,
sodium-carboxy methyl cellulose, ethyl cellulose, e.g. ethyl cellulose 100,
cellulose acetate,
e.g. cellulose acetate CA-398-10 NF, cellulose acetate phthalate, cellulose
acetate
propionate, cellulose acetate butyrate, cellulose butyrate, cellulose nitrate,
hydroxypropyl
methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate,
acryl
derivatives, e.g. polyacrylates, e.g. cross-linked polyacrylates, methycrylic
acid copolymers,
vinyl polymers, e.g. polyvinyl pyrrolidones, polyvinyl acetates, or polyvinyl
acetate phthalates
and mixtures thereof, as marketed under the trade name Kollidon SRO,
polyethylene glycols,
polyanhydrides, polysaccharides, e.g. xanthans, e.g. xanthan gum,
galactomannan, pectin,
and alginates.
Preferred polymers include hydroxypropyl methyl cellulose, e.g. Methocel
K100LV, Methocel
K4M and Methocel K100M.
The polymer comprises from about 10% to about 60% by weight of the composition
of the,
e.g. from about 30% to about 60% by weight of the composition.
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In certain exemplary embodiments of the present invention, the pharmaceutical
composition
may comprise additional excipients commonly found in pharmaceutical
compositions,
examples of such excipients include, but are not limited to glidants,
lubricants, antioxidants,
antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavors,
sweeteners and
other components, e.g. as described in Handbook of Pharmaceutical Excipients,
Rowe et al.,
Eds., 4th Edition, Pharmaceutical Press (2003), which is hereby incorporated
by reference.
These additional excipients may comprise from about 0.05-11% by weight of the
total
pharmaceutical composition, e.g. from about 0.5 to about 2% by weight of the
total
composition. Antioxidants, anti-microbial agents, enzyme inhibitors,
stabilizers or
preservatives typically provide up to about 0.05-1 % by weight of the total
pharmaceutical
composition. Sweetening or flavoring agents typically provide up to about 2.5%
or 5% by
weight of the total pharmaceutical composition.
Suitable lubricant include, but are not limited to magnesium stearate, talc ,
hydrogenated
castor oil, glycerylbehaptate, glycerolmonostearate, polyethylene glycol,
ethylene oxide
polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate,
sodium stearyl
fumarate, DL-leucine, colloidal silica, and others known in the art. The
compositions of the
invention may comprise between about 0 and 3%, e.g. between about 0.5 and 3 %,
e.g. 1 %
lubricant by weight of the composition.
Suitable fillers include, but are not limited to lactose, e.g. in an anhydrous
or hydrated form,
sugar, starches, e.g. corn, wheat, maize or potato starch, modified starches,
e.g. starch
hydrolysates or pregelatinized starch, mannitol, sorbitol, trehalose, maltose,
glucose
anhydrate; inorganic salts, e.g. calcium carbonate, magnesium carbonate,
dibasic calcium
phosphate, tribasic phosphate, or calcium sulfate, microcrystalline cellulose,
cellulose
derivates and others known in the art. The compositions of the invention may
comprise
between about 0 and 65%, e.g. between about 3 and 65% filler by weight of the
composition.
Suitable glidants include but are not limited to Aerosil 200 or talc and
others known in the
art. The compositions of the invention may comprise between about 0 and 2 %
glidant by
weight of the composition.
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Suitable binders include but are not limited to polyvinylpyrrolidone (PVP),
e.g. PVP K30 or
PVP K12, as known and commercially available under the trade name Povidone
from the
BASF company; or hydroxypropylmethylcellulose (HPMC), e.g. HMPC with a low
apparent
viscosity, e.g. below 100 cps as measured at 20 C for a 2 % by weight aqueous
solution,
e.g. below 50 cps, preferably below 20 cps, for example HPMC 3 cps, as known
and
commercially available under the name Pharmacoat 603 from the Shin-Etsu
company. The
compositions of the invention may comprise between about 0 and 5 %, e.g.
between about
0.5 and 5% binder by weight of the composition.
Examples of antioxidants include, but are not limited to, ascorbic acid and
its derivatives,
tocopherol and its derivatives, butyl hydroxyl anisole and butyl hydroxyl
toluene. Vitamin E as
a-tocopherol is particularly useful.
In a further aspect of the present invention, there is provided a process for
preparing a
pharmaceutical composition, e.g., in the form of minitablets as described
hereinabove, which
process comprises mixing the active ingredient, the organic acid, the polymer,
and any
additional tableting excipients, and wet granulating with water or organic
solvents. The dried
granules for the preparation, e.g., in form of the minitablets, may be sieved
through a 400
pm sieve. The outer phase, consisting of silicon dioxide, e.g. as available
under the trade
name Aerosil, and magnesium stearate, may be added and mixed thoroughly. The
blend
may be compressed into minitablets of a diameter of e.g. 1.5 to about 4 mm,
e.g. 1.7 to 2
mm. Resulting minitablets may be encapsulated in a capsule, e.g. hard gelatin
or starch
capsule, or provided in a sachet.
In yet a further aspect of the present invention, there is provided a process
for preparing a
pharmaceutical composition, e.g. in the form of pellets as described
hereinabove, which
process comprises making a dry blend by mixing the active ingredient, the
organic acid, the
polymer and e.g. microcrystalline cellulose in a planetary mixer. Purified
water may be added
to give a wet mass that is subsequently extruded using a screen of a suitable
size. The
extrudates may be rounded in a spheroniser, thoroughly dried and sieved for
suitable size
selection, obtaining e.g. short duration modified release pellets.
In a further embodiment of the invention an enteric coating is applied to the
minitablets or
pellets.
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As used herein the term "enteric coating" refers to a coating which protects
the dosage form
from dissolving already in the stomach, e.g. at pH 1 to 2 up to pH 5.
The enteric coating according to the invention may include the following
(percentages relate
to % of final coated minitablets or pellets)
= 2-40% polymers for enteric coating, e.g. Hydroxypropylmethylcellulose
phthalate, e.g. as
known under the trade name HP 50 or HP 55 and commercially available from Shin
Etsu,
Hydroxypropylmethylcellulose acetate succinate, e.g. as commercially available
under the
trade name Aqoat H, M, or L from Shin Etsu, Methyl acrylic acid - ethyl
acrylic acid
Copolymer (Methacrylic acid copolymer, USP), e.g. as commercially available
under the
trade name Eudragit L, S, L100-55, or L30D from Rohm Pharma, Acryl-Eze from
Colorcon, or Kollicoat MAE 30 DP from BASF, Cellulose acetatephthalate, e.g.
as
commercially available under the trade name Aquacoat CPD from FMC Biopolymer,
or
Polymer from Eastman Kodak, Polyvinylacetatephthalate, e.g. as commercially
available
under the trade name Sureteric from Colorcon
= 0-15% Polymers for subcoating (isolation coat between tablet core and
enteric coat ):
Hydroxypropylmethylcellulose, e.g. as commercially available under the trade
name
Pharmacoat 603 or 606, ethylcellulose, e.g. as commercially available under
the trade
name Aquacoat ECD, FMC Biopolymer, or Surelease from Colorcon, and mixtures
thereof with a ratio of Ethylcellulose:HPMC = 1:1 up to 1:10,
Polyvinylalcohol, e.g. as
commercially available under the trade name Opadry II HP, type 85Ffrom
Colorcon)
= 0-10% plasticizers, e.g. triacetine, triethylcitrate, PEG 4000, PEG 6000,
PEG 8000,
Diethylphthalate, Diethylsebacate, Acetyltriethylcitrate, etc.
= 0-15% antisticking agents, e.g. silicon dioxide, e.g. as commercially
available under the
trade name Aerosil 200, Syloid 244 FP, Talcum, Glycerolmonostearate, etc.
= organic solvents or mixtures thereof with and without parts of water, e.g.
ethanol,
acetone, isopropanol, or water as needed to dissolve or disperse the coating
polymers
and excipients for coating solution
= 0-0.5 % sodium hydroxide for redispersion of polymers for aqueous enteric
coating
suspensions, e.g. for redispersion of Eudragit L100-55.
In a further aspect the present invention provides for a process for coating
of a
pharmaceutical composition as defined herein, which process may comprise
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In the case of organic enteric coating solution:
(1) dissolving the enteric coating polymer and the plasticizer in an organic
solvent, and
(2) dispersing the antisticking agents.
In the case of coating from aqueous dispersions:
(1) dissolving or finely dispersing the plasticizer in water,
(2) dispersing the antisticking agent, and finally
(3) adding the reconstituted suspension (e.g. Aqoat or Eudragit L 100-55,) or
the
commercially available aqueous polymer dispersion (e.g. Eudragit L 30D, Acryl-
Aze,
Kollicoat MAE 30 D).
Optionally an isolation coat may be applied comprising, e.g., an aqueous
solution of a
suitable polymer, e.g. Hydroxypropylmethylcellulose (HPMC) (4-8%), plasticizer
(0-3%) and
antisticking agent (0-3%). An aqueous ethylcellulose dispersion, e.g. Aquacoat
ECD or
Surelease, may be added in the range of 1:10 up to 1:1 (Ethylcellulose : HPMC)
to improve
the isolation effect of the subcoating. Based on the minitablet/pellet size
the total amount of
subcoat applied may be between 3-15% (more probably 5-10%). Polyvinylalcohol
(Opadry II
HP) in a range of 2-10% of core weight may be employed for an effective
subcoating.
In a further aspect, a HPMC subcoat may be applied in form of an organic
suspension in
ethanol/acetone 1:1 (about 6-10% polymer per solvent) without any further
additives.
The enteric coating and/or subcoat may be applied using a pan coater or
fluidized bed
coater with or without Wurster principle up to a coating layer between 2 and
45 % by weight
of the dosage form, .e.g. between about 10-25%, e.g. for large tablets, e.g.
having a
diameter of between about 5 and 15 mm, and between about 20-40%, e.g. for
small tablets,
e.g. minitablets, e.g. having a diameter of between about 1.5 and 4 mm, e.g
between 1.7
and 2 mm. The subcoating layer may comprise between about 2-15% by weight of
the
dosage form, e.g. between about 4-10%, e.g. for large tablets, and between
about 8-15%,
e.g. for small tablets, e.g. minitablets, or pellets. The enteric coating
layer may comprise
between about 5-40% by weight of the dosage form, e.g. between about 8-20%,
e.g. for
large tablets, and between about 15-30%, e.g. for small tablets, e.g.
minitablets, or pellets:
The layer may depend on the minitablet/ pellet size to assure an enteric
resistance for 1-3
hours in artificial gastric juice or 0.1 n HCL solution (acc. to Ph Eur. or
USP). Additionally,
swelling of the core during gastric resistance test should be reduced to a
minimum.
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In a further aspect the present invention provides for a pharmaceutical
composition as
defined hereinabove providing a complete drug release, e.g. complete
disintegration of the
dosage form, within up to 4 hours, e.g. upon contact with gastrointestinal
juices, e.g in the
stomach in the case of non-enteric coated dosage forms, or in the upper part
of the intestinal
tract, e.g. the small intestine, in the case of enteric coated dosage forms.
For example
complete drug release may be provided within about 1 to 4 hours, e.g. within 1
to 3 or 1 to 2
hours, or within about 2 to 4, e.g. 2 to 3 hours.
The utility of all the pharmaceutical compositions of the present invention
may be observed
in standard clinical tests in, e.g., known indications of drug dosages giving
therapeutically
effective blood levels of drug, e.g., using dosages in the range of 2.5-1000
mg of drug per
day for a 75 kg mammal, e.g., adult and in standard animal models. The
increased
bioavailability of the drug provided by the compositions may be observed in
standard animal
tests and in clinical trials.
The following examples are illustrative, but do not serve to limit the scope
of the invention
described herein. The examples are meant only to suggest a method of
practicing the
present invention. Quantities of ingredients, represented by percentage by
weight of the
pharmaceutical composition, used in each example are set forth in the
respective tables
located after the respective descriptions.
Examples
1. Minitablets
The drug, the organic acid, the polymer, and any additional tableting
excipients, are mixed
and wet granulated with water or organic solvents in a mortar. After drying at
40 C, the dried
granules for the preparation of the minitablets are sieved through a 400 pm,
sieve. The outer
phase, comprising silicon dioxide and magnesium stearate, is added and mixed
thoroughly.
The blend is compressed into minitablets having a diameter of 1.7 to 2 mm.
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Exam le 1 ~ ~
-~--------------*-----------
--- --- ------------
------------j----~%~ tnq/capsule
---------- -
Methocel K100LV 1 30.00 ~ 75.00
-- -------=- -L-
--------- ---- --------- -----------
Dipyridam10.00_ 25.00
Fumaric acid ~ 2Q.00 -} 50.00
--------~~~~----------T---~~
Lactose 200 mesh ; 34.00 85.00
-----------=-- -=--
----------- -------- --------
HPMC 3cps 2.676_68
13.33
-133
il 200 ____} 200 500
A-
- Example 2
~~---- ----------T------------
~ / rn /ca sule
----------------------- ---~-~ ~---~-~---P ----
Methocel K100LV~~ 30.00 75.00
----~~~~~ ~~-- ------- --~~~~--~~-
---------L-- 1
Dipyridamole ------------- 10.00 1 25.00
Fumaric acid f 40.00 -t 100.00
Lactose 200 mesh 14.00 ; 35.00
-------------=- -~--
----------- -------- --------
HPMC 3cin ----------a-- 2-67--;---8-68 ---
M~_Stearate__________ 1.33 3.33
------ ----------
L -- j --
Aerosil 200 1 2.00 5.00
-------- F---------~------------
; 100.00 250.00
Exam le 3 '
--p---------------- --------------------------
______' %j rng/ca sule
------------------ ---- -- ----=-- ---p--
Methocel K100LV 30.00 75.00
-- --- --L- -=-
------ ------- ---- ---------- -----------
Lactose 200 mesh 54.00 ~ 135.00
t----------+------------
----------------------
ipyridamole _________ ___10.00___ ___25.00
Fumaric acid 0.00 0.00
-------------=-- --+--
----------- -------- --------
HPMC 3c __________~___ 2_67 6 68
M~_Stearate__________ 1.33 3.33
-------- -------- -
-- --=--
Aerosi1200 2.00 5.00
------------------------F------------+------------
; 100.00 250.00
------------------------.---------------------=_---
Examle 4
----- ______ __ j%] -, ng/c-apSule
- -
Methocel K100LV 30.00 75.00
-- ------- -=-- -=-- -
--------- ---- - --------- ---------
Dipyridamole 10.00 25.00
--i--
-------~~ ----------
Succinic acid 20.00 50.00
------------------------t------------ ------------
Lactose 200 mesh ; 34.00 85.00
HPMC Ic
3cs ___ 2_67 __6.68 -------
Mg_Stearate1.33 3.33
L-- --a-- -
-------- -------- -
Aerosil 2
2.00 5.00
-
~------------
250.00
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Example
--------------- ----------- .------------
j%j -ma/capsule
--------------- ---- - -- --=-- -------
Methocel K100LV 30.00 75.00
-- ------- L --
--------- ---- - ---------- =
----------
Dipyridamole10 00 125.00
Succinic acid F 40.00 -t 100.00
- --------- --------r--- -- -r--_--------_
Lactose 200 mesh 14.00 35.00
------------- -- --+-- -
----------- -------- -------- -
HPMC 3cps ......... '2_67 .6-.65.00
-----250.00
Example 6
- ---------------r------------------------
j%j ---m0%a sule
------ ---------- --- -- - -- ---
-- ------ - -=- -~-
Methocel K4M 30.00 75.00
---------L-- -=-
--------- ---- --------- -----------
Dipyridamole_________~ 10 00 25.00
Fumaric acid } 20.00 t 50.00
--------------------------_--------T_----------_
Lactose 200 r
mesh 34.00 84.99
- -- -- -- --+--
----------- --- --- ------
HPMC 3ces ......... j2:67 6.68 M~_Stearate_----_----}---1_33 __ 3 33
Aerosi1200 5.00
------------------------F------------+------------
; 100.00 250.00
2. Pellets:
A dry blend is made by mixing the active ingredient, the organic acid, the
polymer
and e.g. microcrystalline cellulose in a planetary mixer. Purified water is
added to give
a wet mass that is subsequently extruded using a screen of a suitable size.
The
extrudates are rounded in a spheroniser, thoroughly dried and sieved for
suitable size
selection, obtaining short duration modified release pellets.
Examele 7 % w/w mq
/capsule_
Methocel K100M 30
-------------------+---------------+75
---------------
10 25
Fumaric acid 20 t 50
------------------ ---------------t---------------
Lactose
monohydrate 200,
mesh 40 E 100
3. Enteric coating:
Examples 1 to 4:
Preparation of subcoat:
The subcoat is prepared from an aqueous solution of polymer, plasticizer and
antisticking agent. Optionally an aqueous ethylcellulose dispersion (Aquacoat
ECD or
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Surelease) is added. Alternatively, an organic suspension of polymer in water
or
ethanol/acetone 1:1 is prepared.
Preparation of enteric coat:
In case of an organic enteric coating solution, after dissolving the enteric
coating
polymer and the plastisizer in organic solvents, the antisticking agents are
dispersed.
In case of a coating from aqueous dispersions, the plasticizer is dissolved or
finely
dispersed in water, the antisticking agent is dispersed, and finally the
reconstituted
suspension (i.e. Aqoat or Eudragit L 100-55,) or the commercially available
aqueous
polymer dispersion (Eudragit L 30D, Acryl-Aze, Kollicoat MAE 30 D) are added.
Coating process:
The coating is applied using a pan coater or fluidized bed coater with or
without
Wurster principle up to a coating layer between 2 and 45 % (about 10-25% for
large
tablets and 20-40% for small tablets/minitablets). Subcoating layer: 2-15%
(large
tablets 4-10%, minitablets/pellets: 8-15%) / enteric coating layer: 5-40%(
large tablets:
8-20%, minitablets/pellets: 15-30%) The layer depends on the minitablet/pellet
size to
assure an enteric resistance for 1-3 hours in artificial gastric juice or 0.1
n HCL solution
(acc. to Ph Eur. or USP). Additionally, swelling of the core during gastric
resistance
test is reduced to a minimum.
Example 1 parts % mg/ mg/
250 mg core 8 mg core
Subcoat
HPMC 3 cps 5.0 25.0 12.50 0.80
Trietylcitrate 0.5 2.5 1.25 0.08
Talc 0.5 2.5 1.25 0.08
Water g.s.
Enteric coat
Eudragit L 30 D (dry) 10.0 50.0 25.00 1.60
PEG 6000 2.0 10.0 5.00 0.32
Syloid 244 FP 2.0 10.0 5.00 0.32
Water g.s
Total (dry) 20.0 100. 50.00 3.20
0
Example 2 parts % mg/ mg/
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250 mg core 8 m core
Subcoat
HPMC 3 cps 6.0 26.67 15.0 0.960
Aguacoat ECD (dry) 2.0 8.89 5.0 0.320
Trie citrate 0.6 2.67 1.5 0.096
GLycerinemonostearat 0.4 1.77 1.0 0.064
e
Water g.s.
Enteric coat
HPMC AS A oat MF 10.0 44.44 25.00 1.600
Triethylcitrate 2.5 11.11 6.25 0.400
Talc 1.0 4.44 2.5 0.160
Water g.s.
Total (dry) 22.5 100.0 56.25 3.600
Example 3 parts % mg/ mg/
250 mg core 8 mg core
Subcoat
HPMC 3 cps 5.0 32.5 12.5 0.80
Ethanol/Acetone 1.1:
g.s.
Enteric coat
HP 50 8.0 51.9 20.0 1.28
Triacetine 0.8 5.2 2.0 0.13
Aerosi1200 1.6 10.4 4.0 0.26
Ethanol/Acetone 1:1
g.s.
Total (dry) 15.4 100.0 38.5 2.47
Example 3b parts % mg/ mg/
250 mg core 8 mg core
Enteric coat
HP 50 10 71.43 25.0 1.60
Dieethylsebacate 1 7.14 2.5 0.16
Talc 3 21.43 7.5 0.48
Ethanol/Acetone 1:1
s.
Total dry 14 100.0 34.0 2.24
Example 4 parts % mg/ mg/
250 mg core 8 m core
Subcoat
O ad II HP 4.00 21.46 10.00 0.640
Water g.s.
Enteric coat
Eudragit L100-55 10.00 53.65 25.00 1.600
Sodium hydroxide 0.14 0.75 0.35 0.022
Triethylcitrate 2.50 13.41 6.25 0.400
Syloid 244 FP 2.00 10.73 5.00 0.320
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Water g.s
Total dry 18.64 100.0 46.60 2.982
Example 4b Parts % mg/ mg/
250 mg core 8 mg core
Enteric coat
Eudragit L 100-55 10 76.92 25.0 1.60
Trieth citrate 1 7.69 2.5 0.16
Syloid 244 FP 2 15.38 5.0 0.32
Isopropanol / Water
97:3 g.s
Total dry 13 100.0 32.5 2.08
4. In vitro dissolution studies
Dissolution studies are conducted in USP 1 apparatus (100 rpm, 37 C, and 500ml
dissolution medium). Tablets are exposed to a constant pH medium (phosphate
buffer,
pH=6.8) for a time interval of 6 hours. 0.1 % SDS is added to the buffer to
create sink
conditions. At predetermined intervals samples are withdrawn from the
dissolution medium
and filtered through 0.45 pm membrane filters. Dipyridamole is analyzed
spectrophotometrically at a wavelength of 410 nm (Perkin Elmer UVNIS), whereas
acid
release is quantified by HPLC. An equivalent amount of fresh buffer is added
to maintain a
constant dissolution volume. All experiments are performed in triplicate.
HPLC-Assay
The chromatography is carried out on Agilent HPLC, HP1100, equipped with
Chromeleon
software for data analysis. During the first 8 minutes, the mobile phase
consists of 0.1 M
NH4H2PO4 buffer adjusted to pH 2.7 with phosphoric acid. Subsequently, a
gradient
(acetonitrile/ NH4H2PO4 buffer (pH 2.7)) is used to remove possibly remaining
drug
compound completely. Separation is achieved by using an lnertsil C8-3.5 pm,
4.6*150 mm
(Erchatech AG, Switzerland). A flow rate of 1 ml/min, an injection volume of 5
pL (FA) and
10 pL (CA and SA), and run times of 15 min are applied. Chromatograms are
recorded at
210 nm.
4.1 Simultaneous release of drug compound Dipyridamole 10% (Dipyridamole shown
as
open triangles in Fig. 1) and fumaric acid (variable concentration) (fumaric
acid shown as
filled circles in Fig. 1) from Methocel K4M 30% based tablets is demonstrated
in Fig. 1.
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Dissolution conditions: a) Phosphate buffer pH 6.8, SDS 0.1 %; b) 0.01 N HCI.
The drug is
analysed by UV spectrometry (wavelength: 410 nm), fumaric acid by HPLC
4.2 The impact of pH modifiers (fumaric acid 20% w/w shown as filled circles,
succinic acid
20% w/w shown as filled triangle, and without acid shown as open circles in
Fig. 2) on
release of drug compound (Dipyridamole 10%) from Methocel K100LV 30% based
tablets is
demonstrated in Fig. 2. Dissolution conditions: Phosphate buffer pH 6.8; SDS
0.1%. The
drug is analysed by UV spectrometry (wavelength: 410 nm).
4.3 pH-Independence of drug release with and without fumaric acid (with
fumaric acid (pH
6.8) shown as open triangle, with fumaric acid (pH 2) shown as filled triangle
and without
fumaric acid (pH 2) shown as open squares in Fig. 3) is demonstrated in Fig.
3. Dissolution
conditions: a) Phosphate buffer pH 6.8, SDS 0.1%; b) 0.01 N HCI
The drug is analysed by UV spectrometry (wavelength: 410 nm).
The dissolution of a pH dependent drug compound is enhanced at higher pH
environments.
Incorporation of pH modifiers, e.g. fumaric acid, may shift the pH inside and
in the closest
vicinity of the solid dosage form, e.g. minitablets/pellets, towards being
more acidic, thus
enhancing the drug solubility and dissolution. The polymer helps to maintain
the target pH
within and around the dosage form. Simultaneous release rates of the drug and
the pH
modifier is achieved throughout the entire dissolution.
It is understood that while the present invention has been described in
conjunction with the
detailed description thereof that the foregoing description is intended to
illustrate and not
limit the scope of the invention, which is defined by the scope of the
following claims. Other
aspects, advantages and modifications are within the scope of the claims.
